Posts tagged neurodegenerative diseases
Articles and news from the latest research reports.
New front in war on Alzheimer’s, other protein-folding diseases
A surprise discovery that overturns decades of thinking about how the body fixes proteins that come unraveled greatly expands opportunities for therapies to prevent diseases such as Alzheimer’s and Parkinson’s, which have been linked to the accumulation of improperly folded proteins in the brain.
“This finding provides a whole other outlook on protein-folding diseases; a new way to go after them,” said Andrew Dillin, the Thomas and Stacey Siebel Distinguished Chair of Stem Cell Research in the Department of Molecular and Cell Biology and Howard Hughes Medical Institute investigator at the University of California, Berkeley.
Dillin, UC Berkeley postdoctoral fellows Nathan A. Baird and Peter M. Douglas and their colleagues at the University of Michigan, The Scripps Research Institute and Genentech Inc., will publish their results in the Oct. 17 issue of the journal Science.
Cells put a lot of effort into preventing proteins – which are like a string of beads arranged in a precise three-dimensional shape – from unraveling, since a protein’s activity as an enzyme or structural component depends on being properly shaped and folded. There are at least 350 separate molecular chaperones constantly patrolling the cell to refold misfolded proteins. Heat is one of the major threats to proteins, as can be demonstrated when frying an egg – the clear white albumen turns opaque as the proteins unfold and then tangle like spaghetti.
Heat shock
For 35 years, researchers have worked under the assumption that when cells undergo heat shock, as with a fever, they produce a protein that triggers a cascade of events that field even more chaperones to refold unraveling proteins that could kill the cell. The protein, HSF-1 (heat shock factor-1), does this by binding to promoters upstream of the 350-plus chaperone genes, upping the genes’ activity and launching the army of chaperones, which originally were called “heat shock proteins.”
Injecting animals with HSF-1 has been shown not only to increase their tolerance of heat stress, but to increase lifespan.
Because an accumulation of misfolded proteins has been implicated in aging and in neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases, scientists have sought ways to artificially boost HSF-1 in order to reduce the protein plaques and tangles that eventually kill brain cells. To date, such boosters have extended lifespan in lab animals, including mice, but greatly increased the incidence of cancer.
Dillin’s team found in experiments on the nematode worm C. elegans that HSF-1 does a whole lot more than trigger release of chaperones. An equal if not more important function is to stabilize the cell’s cytoskeleton, which is the highway that transports essential supplies – healing chaperones included – around the cell.
“We are suggesting that, rather than making more of HSF-1 to prevent diseases like Huntington’s, we should be looking for ways to make the actin cytoskeleton better,” Dillin said. Such tactics might avoid the carcinogenic side effects of upping HSF-1.
Dillin is codirector of the Paul F. Glenn Center for Aging Research, a new collaboration between UC Berkeley and UC San Francisco supported by the Glenn Foundation for Medical Research. Center investigators will study the many ways that proteins malfunction within cells, ideally paving the way for novel treatments for neurodegenerative diseases.
A cell at war
Dillin compares a cell experiencing heat shock to a country under attack. In a war, an aggressor first cuts off all communications, such as roads, train and bridges, which prevents the doctors from treating the wounded. Similarly, heat shock disrupts the cytoskeletal highway, preventing the chaperone “doctors” from reaching the patients, the misfolded proteins.
“We think HSF-1 not only makes more chaperones, more doctors, but also insures that the roadways stay intact to keep everything functional and make sure the chaperones can get to the sick and wounded warriors,” he said.
The researchers found specifically that HSF-1 up-regulates another gene, pat-10, that produces a protein that stabilizes actin, the building blocks of the cytoskeleton.
By boosting pat-10 activity, they were able to cure worms that had been altered to express the Huntington’s disease gene, and also extend the lifespan of normal worms.
Dillin suspects that HSF-1’s main function is, in fact, to protect the actin cytoskeleton. He and his team mutated HSF-1 so that it no longer boosted chaperones, demonstrating, he said, that “you can survive heat shock with the normal level of heat shock proteins, as long as you make your cytoskeleton work better.”
He noted that the team’s results – that boosting chaperones is not essential to surviving heat stress – were so contradictory to current thinking that “I made my post-docs’ lives hell for three years” insisting on more experiments to rule out errors. Yet, when Dillin presented the results recently to members of the protein-folding community, he said the first reaction of many was, “That makes perfect sense.”
Aluminium and its likely contribution to Alzheimer’s disease
A world authority on the link between human exposure to aluminium in everyday life and its likely contribution to Alzheimer’s disease, Professor Christopher Exley of Keele University, UK, says in a new report that it may be inevitable that aluminium plays some role in the disease.
He says the human brain is both a target and a sink for aluminium on entry into the body – “the presence of aluminium in the human brain should be a red flag alerting us all to the potential dangers of the aluminium age. We are all accumulating a known neurotoxin in our brain from our conception to our death. Why do we treat this inevitability with almost total complacency?”
Exley, Professor in Bioinorganic Chemistry, Aluminium and Silicon Research Group in The Birchall Centre, Lennard-Jones Laboratories at Keele University, writes in Frontiers in Neurology about the ‘Aluminium Age’ and its role in the ‘contamination’ of humans by aluminium. He says a burgeoning body burden of aluminium is an inevitable consequence of modern living and this can be thought of as ‘contamination’, as the aluminium in our bodies is of no benefit to us it can only be benign or toxic.
Professor Exley says: “The biological availability of aluminium or the ease with which aluminium reacts with human biochemistry means that aluminium in the body is unlikely to be benign, though it may appear as such due to the inherent robustness of human physiology. The question is raised as to ‘how do you know if you are suffering from chronic aluminium toxicity?’ How do we know that Alzheimer’s disease is not the manifestation of chronic aluminium toxicity in humans?
“At some point in time the accumulation of aluminium in the brain will achieve a toxic threshold and a specific neurone or area of the brain will stop coping with the presence of aluminium and will start reacting to its presence. If the same neurone or brain tissue is also suffering other insults, or another on-going degenerative condition, then the additional response to aluminium will exacerbate these effects. In this way aluminium may cause a particular condition to be more aggressive and perhaps to have an earlier onset - such occurrences have already been shown in Alzheimer’s disease related to environmental and occupational exposure to aluminium.”
Professor Exley argues that the accumulation of aluminium in the brain inevitably leads to it contributing negatively to brain physiology and therefore exacerbating on-going conditions such as Alzheimer’s disease. He suggests that this is a testable hypothesis and offers a non-invasive method of the removal of aluminium from the body and the brain. He says the aluminium hypothesis of Alzheimer’s disease will only be tested if we are able to lower the body and hence brain burden of aluminium and determine if such has any impact upon the incidence, onset or aggressiveness of Alzheimer’s disease.
Professor Exley adds: “There are neither cures nor effective treatments for Alzheimer’s disease. The role of aluminium in Alzheimer’s disease can be prevented by reducing human exposure to aluminium and by removing aluminium from the body by non-invasive means. Why are we choosing to miss out on this opportunity? Surely the time has come to test the aluminium hypothesis of Alzheimer’s disease once and for all?”
An enzyme and synaptic plasticity: Study reveals novel role for the Pin1
Synapses are “dynamic” things: they can regulate their action in neural processes related to learning, for example, but also as a consequence of diseases. A research team –led by SISSA– has demonstrated the role of a small enzyme (Pin1) in synaptic plasticity. The study has just been published in the journal Nature Communications.
A small, “empty” space teeming with activity: a synapse is a complex structure where the neural (electrical) signal from the presynaptic neuron, as it travels towards its target –a muscle, a gland or another neuron– turns into a chemical signal capable of crossing the synaptic space before becoming electrical again once on the other side. A synapse is a “dynamic” space not only because of the endless work that goes on there, but also for its ability to change its action over time (synaptic plasticity) as a result of either normal physiological processes (e.g., during learning) or because of disorders due to pathological conditions. A study, mainly carried out by SISSA researchers (which also involved the University of Zurich, LNCIB in Trieste, and EBRI in Rome), showed that a small enzyme (Pin1, peptidylprolyl isomerase) that plays a mediating role in signal transmission has an effect on synaptic plasticity.
The synapse we studied is of the inhibitory kind. The signal it transmits hinders activation of the postsynaptic neuron, making it less likely for it to become activated and emit its action potential”, explains Paola Zacchi, a SISSA researcher who coordinated the study. “When Pin1 is absent from the synapse, signal transmission occurs “at full strength”, but also without control. Instead, when it is present, it regulates signal strength, making it weaker. We observed that Pin1 is able to modify the number of postsynaptic receptors”. The larger the number of receptors capable of binding to the neurotransmitter, the stronger the signal that reaches the postsynaptic membrane. “This also means that Pin1 plays a role in plasticity” explains Zacchi.
How does a synapse work? “A chemical synapse, the most common in vertebrates, is a small gap between nerve cells where the passage of a neural signal occurs”, explains Zacchi. In chemical synapses the two neurons are not in contact but they are separated by a distance of about 20 nanometres. For this reason, the electrical signal travelling along the presynaptic nerve ending is interrupted before resuming on the neuron on the other side of the gap. In between the two nerve cells the electrical signal is translated into a chemical signal (which then becomes electrical again).
“Arrival of the action potential on the presynaptic button causes release, into the interneural space, of molecules of neurotransmitter, which are picked up by receptors on the postsynaptic membrane”, says Zacchi. “If the synapse is excitatory, this leads to postsynaptic activation which, if sufficiently intense, triggers another action potential. If the synapse is inhibitory, as in our studies, the signal suppresses postsynaptic activation and inhibits firing of the electrical potential. In the process of neurotransmitter release and binding, other molecules come into play, such as scaffold proteins, which assemble receptors at the right place on the membrane in front of the neurotransmitter release sites, and neuroligins which act as bridges between the two ends of the synapse as well as interacting with the scaffold proteins. Pin1, the enzyme in the study, interacts with both neuroligins and scaffold proteins.
The Pin1 enzyme has long been known for its role in cancer and the development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s (whereas neuroligins seem to be involved in autism). “Studies like this enhance our understanding of the biochemical mechanisms of synaptic plasticity, extending our knowledge of healthy mechanisms, but also helping those who are trying to understand what can be done in a wide range of pathological conditions”.
Similar but different: new discovery for degenerative disease
Progressive Supranuclear palsy (PSP) and Parkinson’s Disease (PD) have overlapping symptoms but remain difficult to distinguish.
However, a first ever paper on the topic published in the Journal of Neuropsychology (British Psychological Society publication) now suggests that people with PSP experience more severe and extensive cognitive impairments than those with PD early on.
The study indicates that patients with PSP experience more severe and extensive impairments in higher order functions such as planning, abstract thinking, memory retrieval than those with PD.
Lead researcher Dr Young-Eun Claire Lee said the two conditions are so similar that in some cases, patients with PSP often go undiagnosed for the main part of their illness.
“PD and PSP are the two of the most common forms of neurodegenerative diseases resulting in loss of balance and deterioration in mobility,” said Dr Lee.
“Telling these differences apart can be challenging because most patients with PSP do not develop distinctive symptoms such as paralysis or weakness of the eye muscles and episodes of frequent falling until later stages,” she said.
While the study sample was small, the results indicate that cognitive profiles may aid differential diagnosis in earlier stages. PSP claimed the life of musician/actor Dudley Moore.
There are no current treatments for PSP.
Fixing a faulty molecular ‘transport hub’ could slow brain degeneration
University of Queensland researchers have gained new insights into how the body sorts and transports protein ‘cargo’ within our cells, in a finding that could eventually lead to treatments for neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
An international research team co-led by Dr Brett Collins from UQ’s Institute for Molecular Bioscience has revealed the structure of a molecular transport hub that sorts, directs and transports protein to correct destinations in the cell.
Dr Collins said protein cargoes that failed to reach the correct destinations in cells created ‘traffic jams’ that could affect neuronal activity and brain function.
“Having an understanding of how these proteins work together to sort and transport cargo could be the first step in developing drugs that reverse the effects of toxic protein accumulation in neurodegenerative disease,” he said.
Dr Collins has been studying how cargo is sorted, packaged, and trafficked within human cells for more than a decade.
He said that developing drugs that fix faulty proteins such as the transport hub was a relatively new and exciting approach to treatment.
“Traditionally, drugs are developed to try to block or inhibit the function of proteins in the body,” Dr Collins said.
“The problem with drugs that completely stop the function of a protein is that you often get harmful side-effects.”
Dr Collins said the promising finding provided new avenues to target multiple parts of the transport hub to enhance its function by stabilising the protein.
“If we can enhance or improve the function of this protein we could potentially slow down the brain degeneration that occurs in diseases such as Alzheimer’s and Parkinson’s,” he said.
(Source: uq.edu.au)
Turmeric compound boosts regeneration of brain stem cells
A bioactive compound found in turmeric promotes stem cell proliferation and differentiation in the brain, reveals new research published today in the open access journal Stem Cell Research & Therapy. The findings suggest aromatic turmerone could be a future drug candidate for treating neurological disorders, such as stroke and Alzheimer’s disease.
The study looked at the effects of aromatic (ar-) turmerone on endogenous neutral stem cells (NSC), which are stem cells found within adult brains. NSC differentiate into neurons, and play an important role in self-repair and recovery of brain function in neurodegenerative diseases. Previous studies of ar-turmerone have shown that the compound can block activation of microglia cells. When activated, these cells cause neuroinflammation, which is associated with different neurological disorders. However, ar-turmerone’s impact on the brain’s capacity to self-repair was unknown.
Researchers from the Institute of Neuroscience and Medicine in Jülich, Germany, studied the effects of ar-turmerone on NSC proliferation and differentiation both in vitro and in vivo. Rat fetal NSC were cultured and grown in six different concentrations of ar-turmerone over a 72 hour period. At certain concentrations, ar-turmerone was shown to increase NSC proliferation by up to 80%, without having any impact on cell death. The cell differentiation process also accelerated in ar-turmerone-treated cells compared to untreated control cells.
To test the effects of ar-turmerone on NSC in vivo, the researchers injected adult rats with ar-turmerone. Using PET imaging and a tracer to detect proliferating cells, they found that the subventricular zone (SVZ) was wider, and the hippocampus expanded, in the brains of rats injected with ar-turmerone than in control animals. The SVZ and hippocampus are the two sites in adult mammalian brains where neurogenesis, the growth of neurons, is known to occur.
Lead author of the study, Adele Rueger, said: “While several substances have been described to promote stem cell proliferation in the brain, fewer drugs additionally promote the differentiation of stem cells into neurons, which constitutes a major goal in regenerative medicine. Our findings on aromatic turmerone take us one step closer to achieving this goal.”
Ar-turmerone is the lesser-studied of two major bioactive compounds found in turmeric. The other compound is curcumin, which is well known for its anti-inflammatory and neuroprotective properties.
Mouse Model Sheds Light Mitochondria’s Role in Neurodegenerative Diseases
A new study by researchers at the University of Utah School of Medicine sheds light on a longstanding question about the role of mitochondria in debilitating and fatal motor neuron diseases and resulted in a new mouse model to study such illnesses.
Researchers led by Janet Shaw, Ph.D., professor of biochemistry, found that when healthy, functioning mitochondria was prevented from moving along axons – nerve fibers that conduct electricity away from neurons – mice developed symptoms of neurodegenerative diseases. In a study in the Proceedings of the National Academy of Sciences, Shaw and her research colleagues said their findings indicate that motor neuron diseases might result from poor distribution of mitochondria along the spinal cord and axons. First author Tammy T. Nguyen, is a student in the U medical school’s M.D./Ph.D. program, which aims to produce physicians with outstanding clinical skills and rigorous scientific training to bridge the worlds of clinical medicine and basic research to improve health care.
“We’ve known for a long time of the link between mitochondrial function and distribution and neural disease,” Shaw says. “But we haven’t been able to tell if the defect occurs because mitochondria aren’t getting to the right place or because they’re not functioning correctly.”
Mitochondria are organelles – compartments contained inside cells – that serve several functions, including making ATP, a nucleotide that cells convert into chemical energy to stay alive. For this reason mitochondria often are called “cellular power plants.” They also play a critical role in preventing too much calcium from building up in cells, which can cause apoptosis, or cell death.
For mitochondria to perform its functions, it must be distributed to cells throughout the body, which is accomplished with the help of small protein “motors” that transport the organelles along axons. For the motors to transport mitochondria, enzymes known as Mitochondrial Rho (Miro1) GTPases act to attach mitochondria to the motors. To study how the movement of mitochondria is related to motor neuron disease, Nguyen developed two mouse models in which the gene that makes Miro1 was knocked out. In one model, mice lacked Miro1 during the embryonic stage. A second model lacked the enzyme in the cerebral cortex, spinal cord and hippocampus.
The researchers observed that mice lacking Miro1 during the embryonic stage had motor neuron defects that prevented them from taking a single breath once born. After examining the mice, Nguyen, Shaw and their colleagues discovered that neurons required for breathing after birth were missing from the upper half of the mice’s brain stems. The phrenic nerve, also important for breathing, was not fully developed, either.
“We believe the physical difficulties in the mice indicated there were motor neuron defects,” Shaw says.
Conversely, the mice without Miro1 in their brain and spinal cord were fine at birth but soon developed signs of neurological problems, such as hunched spines, difficulty moving and clasping their hind paws together, and died around 35 days after birth. Those symptoms appeared similar to motor neuron disease, according to Shaw.
“The mitochondrial function in the cells appeared to be fine, and calcium levels were normal,” she says. “This shows for the first time that restricting mitochondrial movement and distribution could cause neuronal disease.”
Stefan M. Pulst, M.D., Dr. med, professor and chair of the University’s neurology department and a co-author on the study, says the mitochondrial transport process is important not just for motor neurons but other neurons as well. “The Miro1 proteins and the respective animal models represent a breakthrough for studying ALS (Lou Gehrig’s disease) and other neurodegenerative diseases.”
Although much more research must be done, the study opens the possibility of developing new drugs to partially correct the mitochondrial distribution defects to slow the progression of motor neuron diseases. First, Shaw wants to generate a model to knock out the Miro1 gene in adult mice to see if the results mimic neurological diseases.
Cells Put Off Protein Production During Times of Stress
Living cells are like miniature factories, responsible for the production of more than 25,000 different proteins with very specific 3-D shapes. And just as an overwhelmed assembly line can begin making mistakes, a stressed cell can end up producing misshapen proteins that are unfolded or misfolded.
(Image caption: A color-enhanced electron micrograph shows the nucleus of a cell (blue) adjacent to the rough endoplasmic reticulum (green), where proteins are manufactured from mRNA templates produced by the nucleus. Credit: University of Edinburgh, via the Wellcome TrustAdd)
Now Duke University researchers in North Carolina and Singapore have shown that the cell recognizes the buildup of these misfolded proteins and responds by reshuffling its workload, much like a stressed out employee might temporarily move papers from an overflowing inbox into a junk drawer.
The study, which appears Sept. 11, 2014 in Cell, could lend insight into diseases that result from misfolded proteins piling up, such as Alzheimer’s disease, ALS, Huntington’s disease, Parkinson’s disease, and type 2 diabetes.
“We have identified an entirely new mechanism for how the cell responds to stress,” said Christopher V. Nicchitta, Ph.D., a professor of cell biology at Duke University School of Medicine. “Essentially, the cell remodels the organization of its protein production machinery in order to compartmentalize the tasks at hand.”
The general architecture and workflow of these cellular factories has been understood for decades. First, DNA’s master blueprint, which is locked tightly in the nucleus of each cell, is transcribed into messenger RNA or mRNA. Then this working copy travels to the ribosomes standing on the surface of a larger accordion-shaped structure called the endoplasmic reticulum (ER). The ribosomes on the ER are tiny assembly lines that translate the mRNAs into proteins.
When a cell gets stressed, either by overheating or starvation, its proteins no longer fold properly. These unfolded proteins can set off an alarm — called the unfolded protein response or UPR – to slow down the assembly line and clean up the improperly folded products. Nicchitta wondered if the stress response might also employ other tactics to deal with the problem.
In this study, Nicchitta and his colleagues treated tissue culture cells with a stress-inducing agent called thapsigargin. They then separated the cells into two groups — those containing mRNAs associated with ribosomes on the endoplasmic reticulum, and those containing mRNAs associated with free-floating ribosomes in the neighboring fluid-filled space known as the cytosol.
The researchers found that when the cells were stressed, they quickly moved mRNAs from the endoplasmic reticulum to the cytosol. Once the stress was resolved, the mRNAs went back to their spots on the production floor of the endoplasmic reticulum.
“You can slow down protein production, but sometimes slowing down the workflow is not enough,” Nicchitta said. “You can activate genes to help chew up the misfolded proteins, but sometimes they are accumulating too quickly. Here we have discovered a mechanism that does one better — it effectively puts everything on hold. Once things get back to normal, the mRNAs are released from the holding pattern.”
Interestingly, the researchers found that shuttling ribosomes between the ER and the cytoplasm during stress only affected the subset of mRNAs that would give rise to secreted proteins like hormones or membrane proteins like growth factor receptors — the types of proteins that set off the stress response if they’re misfolded. They aren’t sure yet what this means.
Nicchitta is currently searching for the factors that ultimately determine which mechanisms cells employ during the stress response. He has already pinpointed one promising candidate, and is looking to see how cells respond to stress when that factor is manipulated.
(Source: today.duke.edu)
Brain injuries no match for sPIF treatment
Researchers at Yale School of Medicine and their colleagues have uncovered a new pathway to help treat perinatal brain injuries. This research could also lead to treatments for traumatic brain injuries and neurodegenerative disorders such as Alzheimer’s and Parkinson’s.
The findings are published in the Sept. 8 issue of Proceedings of the National Academy of Sciences.
The MicroRNA molecule let-7 is known to cause the death of neurons in the central nervous system. The research team found that a synthetic molecule derived from the embryo called PreImplantation Factor (sPIF) protects against neuronal death and brain injury by targeting let-7.
“We would never have connected the dots between PIF and let-7 without prior knowledge and experience on let-7 and H19, a developmentally regulated gene that is highly expressed in the developing embryo,” said senior author Dr. Yingqun Huang, associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.
Using a rat perinatal brain injury model, Huang and the team found that sPIF rescued damaged neurons and reduced inflammation. The team performed a series of in vivo and in vitro experiments and found that sPIF helped to stop the production of let-7. “We showed that sPIF works by destabilizing the key microRNA processing protein called KH-type splicing regulatory protein,” said Huang.
Lead author Martin Mueller, who helped develop the rat perinatal brain injury model, was surprised at the consistency of the results from both the in vivo and in vitro studies. “Collectively, our findings suggest that sPIF mitigates brain damage through a novel pathway,” said Mueller. “We saw more cortical brain volume and more neurons restored in brain damaged animals receiving sPIF.”
“For the first time, we have clear indication to pursue a new line of investigation in the treatment of perinatal brain injury, and possibly traumatic brain injury,” said co-author Dr. Michael Paidas, professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.
Paidas, who is also vice chair of obstetrics at Yale, has helped to identify PIF’s effects with co-author Eytan R. Barnea, founder of the Society for the Investigation of Early Pregnancy (SIEP) and chief scientific officer of BioIncept, LLC. Barnea discovered and characterized PIF and described key elements of its mode of action.
Based on this promising data, the FDA has awarded sPIF fast-track designation and allowed a phase 1 sPIF clinical trial to treat patients with autoimmune liver disease at the University of Miami.
Broken signals lead to neurodegeneration
Researchers from the RIKEN Brain Science Institute in Japan, in collaboration with Juntendo University and the Japan Science and Technology Agency, have discovered that a cell receptor widely involved in intracellular calcium signaling—the IP3R receptor—can be locked into a closed state by enzyme action, and that this locking may potentially play a role in the reduction of neuron signaling seen in neurodegenerative diseases such as Huntington’s and Alzheimer’s disease.
In the research published today in the Proceedings of the National Academy of Sciences, the scientists reported experiments in human cells and a mouse model of Huntington’s disease revealing that transglutaminase type 2—a protein cross-linking enzyme elevated in the cells of patients with neurodegenerative diseases—interacts with the IP3R receptor to lock it in a closed non-functional conformation preventing it from fulfilling its essential calcium-releasing role. They identified a specific amino acid site on the receptor, Gln2746, where the modification takes place, deepening our understanding of how receptors are locked and potentially opening the door to studies on other functional proteins that are also regulated by conformational changes.
The IP3R channel, which is located in the endoplasmic reticulum, a protein assembly and transport compartment, plays a crucial role in intracellular calcium signaling, and is involved in a wide range of cell functions including mitochondrial energy production and the regulation of autophagy, the process through which cells consume and degrade unused components to maintain a healthy balance of functional proteins. Although autophagy is normally a mechanism that sustains cell maintenance, it can also trigger a loss of cell function and has been associated with prominent diseases including Huntington’s disease, Alzheimer’s disease, and Parkinson’s disease.
In this work, the scientists propose a general model under which abnormal IP3R-mediated calcium signaling caused by the action of transglutaminase type 2 leads to cellular dysfunction and subsequently to the emergence of progressive brain dysfunction. Transglutaminase 2 activation is commonly associated with inflammation and stress, and its action on the IP3R channel might provide an explanation for the initiation and progression steps common to different neurodegenerative diseases.
According to Katsuhiko Mikoshiba, who led the study, “We think that the mechanism we identified in this study could provide us with a more general model of other diseases both of the brain and other parts of the body, where transglutaminase type 2 is upregulated. We hope that this insight could eventually lead to the development of new drug therapies for a number of neurodegenerative diseases that place a high burden on patients and society.”